1. Field of the Invention
The invention relates to the preparation of nucleoside analogs for use as antiviral agents. In particular, the invention relates to the synthesis of β-L-5-fluoro-2′,3′-dideoxy-2′,3′-didehydrocytidine (β-L-FD4C).
2. Description of Related Art
Acquired immune deficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) has created an international health crisis. According to the World Health Organization, by the end of the year 2001 an estimated 40 million people worldwide were living with HIV/AIDS. Approximately 5 million of these people became infected with HIV during 2001. HIV/AIDS is the fourth leading cause of death worldwide, resulting in 3 million fatalities in 2001 alone (Weekly Epidemiological Record 76:381-388 (2001)).
Another virus that poses a serious human health problem is the hepatitis B virus (HBV). Besides causing acute hepatitis, HBV can result in chronic infection leading to often-fatal cirrhosis and cancer of the liver. By the year 2000, a reported 2 billion people had been infected with HBV (Fact Sheet WHO/204, World Health Organization (October 2000)).
Various synthetic nucleosides have been identified as potential antiviral agents for treating HIV and HBV. Following the development of 3′-azido-3′-deoxythymidine (AZT) as an HIV therapy (Mitsuya et al., Proc. Natl. Acad. Sci. USA 82:7096-7100 (1985)), several 2′,3′-dideoxy (dd) and 2′,3′-didehydro-2′,3′-dideoxy (D4) nucleosides were identified as potential HIV and HBV treatments. For example, nucleoside analogs approved for clinical use as antiviral agents included 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxycytidine (ddC) (Mitsuya et al., Proc. Natl. Acad. Sci. USA 83:1911-1915 (1986)), and 2′,3′-didehydro-3′-deoxythymidine (D4T) (Mansuri et al., J. Med. Chem. 32:461-466 (1989)). While these nucleoside analogs are used in the form of the naturally-occurring “D” enantiomer, recent developments in the field have focused on several nucleoside analogs having the unnatural “L” configuration. For example, β-L-5-fluoro-2′,3′-dideoxy-3′-thiacytidine (FTC) (Jeong et al., J. Med. Chem. 36:181-195 (1993)), β-L-5-fluoro-2′,3′-dideoxycytidine (β-L-FddC) (Lin et al., Biochem. Pharmacol. 47:171-174 (1994)), and β-L-5-fluoro-2′,3′-dideoxy-2′,3′-didehydrocytidine (β-L-FD4C) (Lin et al., J. Med. Chem. 39:1757-1759 (1996)) have been identified as potential therapies for HIV and HBV.
β-L-FD4C has proven to be an especially promising antiviral agent for treating HIV and HBV (Lin et al., J. Med. Chem. 39:1757-1759 (1996)). Early synthetic methods for preparing β-L-FD4C (Lin et al., J. Med. Chem. 39:1757-1759 (1996)) suffered from low yield, and therefore were unsuitable for large-scale production. Alternative synthetic methods for preparing β-L-FD4C have been proposed (U.S. Pat. No. 6,005,097). However, a need exists in the art for new synthetic methods allowing for efficient, cost-effective, and environmentally sound commercial scale production of β-L-FD4C for use in treating the worldwide epidemics of HIV and HBV.